Systems Biology in Reproductive Medicine, Apr 1, 2010
Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environmen... more Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environment. As a result, exposure to solvents like toluene in work-related settings (i.e., relatively constant, low-level exposures) or through inhalant abuse (i.e., relatively intermittent, high-level exposures) is increasing for many women of reproductive age. Evidence suggests that the risk for pregnancy problems, as well as developmental delays and neurobehavioral difficulties, is higher for the children of women who have been exposed to high concentrations of organic solvents during pregnancy than for those who have not. These risks appear to be higher in cases of abuse exposure to solvents such as toluene, particularly in comparison to the risk for teratogenic outcomes with occupational solvent exposure. Despite this, the reproductive toxicology and teratology following abuse of toluene and other inhalants remains under-investigated. This brief review describes the current state of our understanding of the reproductive and teratogenic risk of gestational toluene abuse. The data to date suggest that the high levels of toluene exposure typical with inhalant abuse are more detrimental to fetal development than typical occupational exposure, and preclinical paradigms can be beneficial for investigating the processes and risks of prenatal solvent exposure. While substantial research has been done on the reproductive effects of occupational exposures to organic solvents, more research is needed on the outcomes and mechanisms of exposures typical of inhalant abuse.
More than 22 million Americans age 12 and older have used inhalants, and every year more than 750... more More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed "the forgotten epidemic." Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, Jan 23, 2015
To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive f... more To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD. B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT(2) Profiler™), radiation-associated cytokines (Milliplex® MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task. Single X-ray doses reduced the number (p=0.002) and size (p=0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6% (1Gy×10), 72% (2Gy×5) and 78% (2Gy×10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p=0.004) and proteomic (MIP-2, 8-fold, p=0.0024) changes at 24-48h. Microglia increased at 4weeks post-irradiation (p=0.001). The reduction in Aβ bur...
More than 22 million Americans age 12 and older have used inhalants, and every year more than 750... more More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed "the forgotten epidemic." Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts.
Binge Toluene Exposure in Pregnancy and Pre-weaning Developmental Consequences in Rats. Bowen, S.... more Binge Toluene Exposure in Pregnancy and Pre-weaning Developmental Consequences in Rats. Bowen, S.E. and Hannigan, J.H. The persistent rate of abuse of inhaled organic solvents, especially among women of child-bearing age, raises the risk for teratogenic effects of maternal toluene abuse. In this study, timed-pregnant Sprague Dawley rats were exposed from Gestation Day (GD) 8 to GD20 to 12,000 or 8000 parts per million (ppm) toluene, or 0ppm (controls) for 30min twice daily, 60min total daily exposure. Pups were assessed from postnatal day (PN) 4 to PN21 using a developmental battery measuring growth (i.e., body weight), maturational milestones (e.g., eye opening & incisor eruption), and biobehavioral development (e.g., negative geotaxis & surface righting). Pups exposed in utero to 12,000ppm or 8000ppm toluene weighed significantly less than the non-exposed control pups beginning at PN4 and PN12 (respectively) until PN21. Toluene resulted in significant increases in an index of poor perinatal outcome, specifically a composite of malformations, defined "runting" and neonatal death. No significant delays were observed in reaching maturational milestones. The results reveal that brief, repeated, prenatal exposure to high concentrations of toluene can cause growth retardation and malformations in rats. A comparison of the present, conservative results with findings in previous studies implies that binge patterns of toluene exposure in pregnant rats modeling human solvent abuse can result in developmental and morphological deficits in offspring. These results do not exclude the possibility that maternal toxicity as well as teratogenic effects of toluene may contribute to outcomes. The results suggest that abuse of inhaled organic solvents like toluene may result in similar early developmental outcomes in humans.
Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environmen... more Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environment. As a result, exposure to solvents like toluene in work-related settings (i.e., relatively constant, low-level exposures) or through inhalant abuse (i.e., relatively intermittent, high-level exposures) is increasing for many women of reproductive age. Evidence suggests that the risk for pregnancy problems, as well as developmental delays and neurobehavioral difficulties, is higher for the children of women who have been exposed to high concentrations of organic solvents during pregnancy than for those who have not. These risks appear to be higher in cases of abuse exposure to solvents such as toluene, particularly in comparison to the risk for teratogenic outcomes with occupational solvent exposure. Despite this, the reproductive toxicology and teratology following abuse of toluene and other inhalants remains under-investigated. This brief review describes the current state of our understanding of the reproductive and teratogenic risk of gestational toluene abuse. The data to date suggest that the high levels of toluene exposure typical with inhalant abuse are more detrimental to fetal development than typical occupational exposure, and preclinical paradigms can be beneficial for investigating the processes and risks of prenatal solvent exposure. While substantial research has been done on the reproductive effects of occupational exposures to organic solvents, more research is needed on the outcomes and mechanisms of exposures typical of inhalant abuse.
Abused solvents have effects similar to those of abused depressant drugs. This experiment evaluat... more Abused solvents have effects similar to those of abused depressant drugs. This experiment evaluated the time course of the discriminative stimulus effects of toluene and 1,1,1-trichloroethane (TRI). Mice were trained to discriminate between i.p. injections of ethanol (EtOH; 1.25 g/kg) and saline in a two-lever operant task in which responding was under the control of a fixed-ratio 20 schedule. After 20-min inhalation exposures to toluene (500-6000 ppm) or TRI (1000-12,000 ppm), stimulus generalization was examined at 0, 5, 10, 20, and 40 min post-exposure. Ethanol doses>or=0.25 g/kg produced increases in EtOH-lever responding with full substitution occurring immediately after testing for doses between 1.25 and 2.5 g/kg. Toluene and TRI produced increased EtOH-lever responding at 0-10 min post-exposure with some EtOH-lever responding occurring up to 20-min post-exposure. Response rates were not decreased for any concentration of toluene or TRI immediately following inhalant exposure but several concentrations elevated rates from 5 to 40 min post-exposure. These results confirm and extend previous studies and show these solvents produce similar effects in EtOH-lever responding but with potency differences. The time-dependent differences in EtOH-lever responding suggest that as solvents are cleared from the body, the EtOH-like subjective effects also fade.
In the present studies, drug discrimination procedures were used to compare the discriminative st... more In the present studies, drug discrimination procedures were used to compare the discriminative stimulus effects of ethanol (ETOH) and several volatile anesthetics. Male albino mice were trained to discriminate between IP injections of ETOH (1.25 g/kg) and saline in a two-lever operant task in which responding was under the control of a fixed-ratio 20 (FR20) schedule of food presentation. Stimulus generalization was examined after 20-min inhalation exposures to desflurane (4,000-32,000 ppm), enflurane (3,000-12,000 ppm), isoflurane (1,000-8,000 ppm) and ether (4,000-32,000 ppm). Concentration-related increases in ETOH-lever responding were observed for all four volatile anesthetics. For enflurane and ether, maximal levels of > 85% ETOH-lever responding were obtained at one or more concentrations. For desflurane and isoflurane, the maximal mean percentages of ETOH-lever responding were somewhat lower, but 6 out of 7 mice showed full substitution with desflurane and 5 out of 7 for isoflurane. The shared discriminative properties of these compounds with ETOH suggest that these anesthetics may share some of ETOH's pharmacological properties. These results are similar to previous research results showing ETOH-like discriminative stimulus effects in mice with other anesthetics and abused volatile inhalants (i.e. halothane, toluene and 1.1,1-trichloroethane) and may reflect the CNS-depressant drug-like effects of inhaled anesthetics and abused solvents.
Systems Biology in Reproductive Medicine, Apr 1, 2010
Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environmen... more Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environment. As a result, exposure to solvents like toluene in work-related settings (i.e., relatively constant, low-level exposures) or through inhalant abuse (i.e., relatively intermittent, high-level exposures) is increasing for many women of reproductive age. Evidence suggests that the risk for pregnancy problems, as well as developmental delays and neurobehavioral difficulties, is higher for the children of women who have been exposed to high concentrations of organic solvents during pregnancy than for those who have not. These risks appear to be higher in cases of abuse exposure to solvents such as toluene, particularly in comparison to the risk for teratogenic outcomes with occupational solvent exposure. Despite this, the reproductive toxicology and teratology following abuse of toluene and other inhalants remains under-investigated. This brief review describes the current state of our understanding of the reproductive and teratogenic risk of gestational toluene abuse. The data to date suggest that the high levels of toluene exposure typical with inhalant abuse are more detrimental to fetal development than typical occupational exposure, and preclinical paradigms can be beneficial for investigating the processes and risks of prenatal solvent exposure. While substantial research has been done on the reproductive effects of occupational exposures to organic solvents, more research is needed on the outcomes and mechanisms of exposures typical of inhalant abuse.
More than 22 million Americans age 12 and older have used inhalants, and every year more than 750... more More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed "the forgotten epidemic." Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, Jan 23, 2015
To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive f... more To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD. B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT(2) Profiler™), radiation-associated cytokines (Milliplex® MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task. Single X-ray doses reduced the number (p=0.002) and size (p=0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6% (1Gy×10), 72% (2Gy×5) and 78% (2Gy×10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p=0.004) and proteomic (MIP-2, 8-fold, p=0.0024) changes at 24-48h. Microglia increased at 4weeks post-irradiation (p=0.001). The reduction in Aβ bur...
More than 22 million Americans age 12 and older have used inhalants, and every year more than 750... more More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed "the forgotten epidemic." Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts.
Binge Toluene Exposure in Pregnancy and Pre-weaning Developmental Consequences in Rats. Bowen, S.... more Binge Toluene Exposure in Pregnancy and Pre-weaning Developmental Consequences in Rats. Bowen, S.E. and Hannigan, J.H. The persistent rate of abuse of inhaled organic solvents, especially among women of child-bearing age, raises the risk for teratogenic effects of maternal toluene abuse. In this study, timed-pregnant Sprague Dawley rats were exposed from Gestation Day (GD) 8 to GD20 to 12,000 or 8000 parts per million (ppm) toluene, or 0ppm (controls) for 30min twice daily, 60min total daily exposure. Pups were assessed from postnatal day (PN) 4 to PN21 using a developmental battery measuring growth (i.e., body weight), maturational milestones (e.g., eye opening & incisor eruption), and biobehavioral development (e.g., negative geotaxis & surface righting). Pups exposed in utero to 12,000ppm or 8000ppm toluene weighed significantly less than the non-exposed control pups beginning at PN4 and PN12 (respectively) until PN21. Toluene resulted in significant increases in an index of poor perinatal outcome, specifically a composite of malformations, defined "runting" and neonatal death. No significant delays were observed in reaching maturational milestones. The results reveal that brief, repeated, prenatal exposure to high concentrations of toluene can cause growth retardation and malformations in rats. A comparison of the present, conservative results with findings in previous studies implies that binge patterns of toluene exposure in pregnant rats modeling human solvent abuse can result in developmental and morphological deficits in offspring. These results do not exclude the possibility that maternal toxicity as well as teratogenic effects of toluene may contribute to outcomes. The results suggest that abuse of inhaled organic solvents like toluene may result in similar early developmental outcomes in humans.
Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environmen... more Toluene is an organic solvent that is widely used by industry and is ubiquitous in our environment. As a result, exposure to solvents like toluene in work-related settings (i.e., relatively constant, low-level exposures) or through inhalant abuse (i.e., relatively intermittent, high-level exposures) is increasing for many women of reproductive age. Evidence suggests that the risk for pregnancy problems, as well as developmental delays and neurobehavioral difficulties, is higher for the children of women who have been exposed to high concentrations of organic solvents during pregnancy than for those who have not. These risks appear to be higher in cases of abuse exposure to solvents such as toluene, particularly in comparison to the risk for teratogenic outcomes with occupational solvent exposure. Despite this, the reproductive toxicology and teratology following abuse of toluene and other inhalants remains under-investigated. This brief review describes the current state of our understanding of the reproductive and teratogenic risk of gestational toluene abuse. The data to date suggest that the high levels of toluene exposure typical with inhalant abuse are more detrimental to fetal development than typical occupational exposure, and preclinical paradigms can be beneficial for investigating the processes and risks of prenatal solvent exposure. While substantial research has been done on the reproductive effects of occupational exposures to organic solvents, more research is needed on the outcomes and mechanisms of exposures typical of inhalant abuse.
Abused solvents have effects similar to those of abused depressant drugs. This experiment evaluat... more Abused solvents have effects similar to those of abused depressant drugs. This experiment evaluated the time course of the discriminative stimulus effects of toluene and 1,1,1-trichloroethane (TRI). Mice were trained to discriminate between i.p. injections of ethanol (EtOH; 1.25 g/kg) and saline in a two-lever operant task in which responding was under the control of a fixed-ratio 20 schedule. After 20-min inhalation exposures to toluene (500-6000 ppm) or TRI (1000-12,000 ppm), stimulus generalization was examined at 0, 5, 10, 20, and 40 min post-exposure. Ethanol doses>or=0.25 g/kg produced increases in EtOH-lever responding with full substitution occurring immediately after testing for doses between 1.25 and 2.5 g/kg. Toluene and TRI produced increased EtOH-lever responding at 0-10 min post-exposure with some EtOH-lever responding occurring up to 20-min post-exposure. Response rates were not decreased for any concentration of toluene or TRI immediately following inhalant exposure but several concentrations elevated rates from 5 to 40 min post-exposure. These results confirm and extend previous studies and show these solvents produce similar effects in EtOH-lever responding but with potency differences. The time-dependent differences in EtOH-lever responding suggest that as solvents are cleared from the body, the EtOH-like subjective effects also fade.
In the present studies, drug discrimination procedures were used to compare the discriminative st... more In the present studies, drug discrimination procedures were used to compare the discriminative stimulus effects of ethanol (ETOH) and several volatile anesthetics. Male albino mice were trained to discriminate between IP injections of ETOH (1.25 g/kg) and saline in a two-lever operant task in which responding was under the control of a fixed-ratio 20 (FR20) schedule of food presentation. Stimulus generalization was examined after 20-min inhalation exposures to desflurane (4,000-32,000 ppm), enflurane (3,000-12,000 ppm), isoflurane (1,000-8,000 ppm) and ether (4,000-32,000 ppm). Concentration-related increases in ETOH-lever responding were observed for all four volatile anesthetics. For enflurane and ether, maximal levels of > 85% ETOH-lever responding were obtained at one or more concentrations. For desflurane and isoflurane, the maximal mean percentages of ETOH-lever responding were somewhat lower, but 6 out of 7 mice showed full substitution with desflurane and 5 out of 7 for isoflurane. The shared discriminative properties of these compounds with ETOH suggest that these anesthetics may share some of ETOH's pharmacological properties. These results are similar to previous research results showing ETOH-like discriminative stimulus effects in mice with other anesthetics and abused volatile inhalants (i.e. halothane, toluene and 1.1,1-trichloroethane) and may reflect the CNS-depressant drug-like effects of inhaled anesthetics and abused solvents.
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